Update in Vitamin DJohn S. Adams and Martin Hewison
University of California-Los Angeles (UCLA)-Orthopaedic Hospital Research Center and Department of Orthopaedic Surgery (J.S.A., M.H.); Department of Molecular,Cell, and Developmental Biology (J.S.A.); Department of Medicine (J.S.A., M.H.); and the Molecular Biology Institute (M.H.), UCLA, Los Angeles, California90095-7358Address all correspondence and requests for reprints to: John S. Adams, M.D., UCLA-Orthopaedic Hospital Research Center, 615 Charles Young Drive South, Room410E, Los Angeles, California 90095-7358. E-mail: [email protected].
The past decade, particularly the last 18 months, witnessed a vigorous increase in interest in vitamin D from both the lay andbiomedical worlds. Much of the growing interest in vitamin D is powered by new data being extracted from the NationalHealth and Nutrition Examination Survey (NHANES). The newest statistics demonstrate that more than 90% of thepigmented populace of the United States (Blacks, Hispanics, and Asians) now suffer from vitamin D insufficiency(25-hydroxyvitamin D <30 ng/ml), with nearly three fourths of the white population in this country also being vitamin Dinsufficient. This represents a near doubling of the prevalence of vitamin D insufficiency seen just 10 yr ago in the samepopulation. This review attempts to provide some explanation for: 1) the rapid decline in vitamin D status in the UnitedStates; 2) the adverse impact of vitamin D insufficiency on skeletal, infectious/inflammatory, and metabolic health inhumans; and 3) the therapeutic rationale and reliable means for vigorous supplementation of our diets with vitamin D.
There is renewed interest in vitamin D synthesis, metabolism, and action. The two principal driving forces for heightenedinterest can be traced to: 1) the worsening, worldwide trend to nutritional vitamin D insufficiency (1,2); and 2) newknowledge regarding the nonhormonal, intracrine, and paracrine actions of 1-hydroxylated vitamin D metabolites in man (3).Annual citations in the PubMed database on vitamin D were approximately 4800 from May 2008 to May 2009. Thisrepresents a doubling in the last decade and a 15% increase in the last year.
The major endogenous, synthetic source of vitamin D for humans is the epidermis. Vitamin D is produced in the skin by aUVB-mediated, photolytic, nonenzymatic reaction that converts 7-dehydrocholesterol to previtamin D (4). Previtamin Dundergoes a subsequent nonenzymatic, thermal isomerization conversion to vitamin D , also in the skin. From the skin,vitamin D finds its way into the general circulation. In the hepatic parenchyma, vitamin D is converted by one of several,high-capacity cytochrome P450s to 25-hydroxyvitamin D (25OHD ); the microsomal CYP2R1 appears to have the highestaffinity for substrate vitamin D (5). 25OHD (see Footnote 1) is the most plentiful and stable metabolite of vitamin D inhuman serum, qualities determined by the heightened affinity by which 25OHD is bound by the serum vitamin D bindingprotein and other members of the albumin superfamily of proteins found in the blood (6). As such, the 25OHD level in theserum is the best indicator of vitamin D (see Footnote 1) entering the host, either by cutaneous synthesis or by ingestion inthe diet. In cross-sectional studies, especially those performed in populations living at relatively elevated latitudes in NorthAmerica, Europe, and Asia, serum levels of the 25OHD metabolite are maximal some 30–60 d after peak sunlight exposurein the summer months. 25OHD is a prohormone or immediate precursor metabolite to the active form of vitamin D,1,25-dihydroxyvitamin D (1,25(OH) D) (see Footnote 1). 1,25(OH) D is the product of a single enzyme, the mitochondrialCYP27B1-hydroxylase, and it serves as a high-affinity ligand for the vitamin D receptor (VDR) in target tissues where it actsto modulate expression of vitamin D-directed genes. 1,25(OH) D circulates in the serum at concentrations that are roughly0.1% that of the prohormone 25OHD.
Figure 1A defines the evolutionarily distinct, but preserved, functions of vitamin D. The more evolutionarily advancedfunction of vitamin D is that of a hormone. This function is reserved for species bearing an endoskeleton where the1,25(OH) D hormone serves as a circulating regulator of both mineral and skeletal homeostasis in the host. The only
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recognized source of the hormone in man is the CYP27B1-hydroxylase; this enzyme is confined principally but not entirelyto the proximal tubular epithelial cell of the kidney. 1,25(OH) D synthesis in the kidney is regulated by other hormones. It isstimulated primarily by PTH and inhibited by circulating fibroblast growth factor 23 (FGF23) made by osteocytes (7).
The more evolutionarily primitive function of vitamin D is that of a cytokine generated to protect the inside environment ofthe host (single cell organisms to man) from microbial invaders in the external environment (8). The 1,25(OH) D cytokine issynthesized primarily by monocyte-macrophages and acts in an intracrine mode via interaction with the VDR to modulatethe innate immune response to invading microbial agents (9). When produced in sufficient quantities, 1,25(OH) D canescape the confines of the monocyte-macrophage to interact with and control the cytokine profiles of activated,VDR-expressing T- and B-lymphocytes in the local, inflammatory microenvironment (8). A key distinction between the1,25(OH) D hormone and cytokine systems is that an inadequate supply of substrate 25OHD will stimulate the renalCYP27B1-hydroxylase to maintain or increase production of the active, 1,25(OH) D metabolite via secondaryhyperparathyroidism, whereas a deficiency of substrate for the extrarenal CYP27B1-hydroxylase leads to a decrease inproduct 1,25(OH) D.
The Problem of Vitamin D Insufficiency (see Footnote 1)
Changes in hormonal vitamin D metabolism and action occur quickly when the human host is required to defend the state ofnormocalcemia in the face of vitamin D insufficiency/deficiency and a reduction in the efficiency of intestinal calciumabsorption. These events are depicted in Fig. 1B. A drop in intestinal calcium absorption results in a small but real decreasein the serum calcium concentration. This decrease is detected by the calcium-sensing receptor embedded in the plasmamembrane of the parathyroid cell. This is a signal to release PTH from the gland and to increase PTH gene expression.Interaction of PTH with the PTH/PTHrP receptor in the plasma membrane of the proximal tubular epithelial cell of thekidney signals an increase in CYP27B1 gene expression and conversion of available substrate 25OHD to 1,25(OH) D.1,25(OH) D finds its way back into the serum and onto a serum vitamin D binding protein, whereby it gains access tocontrol regions (vitamin D responsive elements) of VDR-regulated genes in the gut and bone to: 1) promote intestinalcalcium and phosphate absorption; and 2) liberate calcium and phosphate from the mineral phase of bone, respectively.When the deficit in the serum calcium concentration is corrected by such means, the activated 1,25(OH) D:PTH axis issubsequently down-regulated by FGF23 released from bone (7).
An understanding of the above-stated physiology led Chapuy et al. (10) and subsequently others to define endocrine vitaminD (i.e. 25OHD) insufficiency/deficiency in terms of a significant increase in serum immunoreactive PTH (iPTH) levels. It isnow generally agreed that the serum iPTH will start to rise significantly once the serum 25OHD drops to less than 30 ng/mlor 75 nmol/liter (2); values of 25OHD between 30 ng/ml or 75 nmol/liter and 20 ng/ml or 50 nmol/liter are considered torepresent vitamin D insufficiency, whereas those less than 20 ng/ml or 50 nmol/liter fall into the frankly vitamin D-deficientrange; it is usually only in the latter situation where one is likely to observe clinically apparent skeletal effects of thedeficient state. In the United States, as well as in other parts of the world, the mean populational serum 25OHD levels haveplummeted in the last decade. The best example of this drop comes from the National Health and Nutrition ExaminationSurvey (NHANES) population studied in 1994 and again in 2004 (11). Although these analyses were carried out by the samegroup using the same assay technology, there was some variation in the 25OHD antiserum employed. Nevertheless, theseminor variations in methodology cannot explain the near doubling in the number of subjects in the American populationfrom 1994 to 2004 with 25OHD levels less than 30 ng/ml. Currently, only 20–25% of the assayed NHANES population has aserum 25OHD level of at least 30 ng/ml, whereas 25–35% of the population has frank vitamin D deficiency (i.e. 25OHD <20 ng/ml) (12). This finding holds across all age groups, ages 12 to more than 60 yr, males and females alike. In pigmentedBlack and Latino segments of the population, the percentage of vitamin D-sufficient subjects is less than 10%. In theAmerican Black population, less than 3% of mothers are vitamin D sufficient (11), and the mean cord blood level of 25OHDin the offspring of African-American mothers (10 ± 6 ng/ml) is well into the vitamin D-deficient range (13).
What underlies this dramatic decrease in vitamin D sufficiency? According to Looker et al. (14), the downward trend in25OHD levels in the NHANES population is associated with a significant trend: 1) downward in milk consumption (in theU.S. milk products are artificially fortified with vitamin D); 2) upward in sun protection and sun avoidance; and 3) upward inbody mass index (BMI). There is no doubt that more liberal use of sunscreens, sun avoidance, and milk intake have had arole to play in the descent of the serum 25OHD levels in the last decade in the United States, but this does not really explainthe more exaggerated fall in serum 25OHD of 77% and 69% in pigmented African-American and Latino subpopulations,respectively, in the NHANES. This suggests that obesity, as will be discussed in more detail below, may be an especiallyimportant contributor to the vitamin D insufficient/deficient state in this subgroup of subjects.
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Adverse Outcomes Associated with Vitamin D Insufficiency
Musculoskeletal system
We have known for almost two centuries now that increased sunlight exposure was a critical factor in the correction of mostrachitic syndromes (soft bones and proximal muscle weakness) in man (15). Hence, it is not surprising that in 2008–2009 weobserve a low 25OHD level in the serum to be significantly associated with low bone mineral density (16) and increased riskof nonvertebral (17) and hip fracture (18). For example, results from NHANES III (16) have disclosed that low bone densityin the hip, a surrogate measure of fracture risk at that site, in both men and women is directly related to the serum 25OHDlevel but unrelated to the dietary calcium intake of the host. Furthermore, data from the Women’s Health Initiative (18)indicate that for every 10 ng/ml decrease in the serum 25OHD level there is a significant trend upward in the odds ratio ofrisk for hip fracture (unadjusted and adjusted), with a near doubling of that odds ratio if one has a serum 25OHD in thefrankly vitamin D-deficient range (<20 ng/ml). It is assumed that the decrease in 25OHD leads to a state of persistentsecondary hyperparathyroidism with enhanced osteoclastogenesis and consequent increased bone resorption outstrippingosteoblast-directed bone formation (Fig. 1B). In fact, the consequences of vitamin D deficiency in the mother can beobserved in the fetal skeleton as early as 19 wk of human gestation. Mahon et al. (19) have recently demonstrated a rachiticphenotype in the fetal femur, the severity of which is directly associated with a decreasing 25OHD level in the maternalcirculation.
Microbial disease
Recent studies in humans have emphasized a potential role for the vitamin D monokine system as a necessary intermediate inthe generation of antimicrobial peptides by monocyte-macrophages (9). In these and subsequent experiments with humanmonocyte-macrophages (8,20,21,22), it is now clear that activation of the Toll-like receptor (TLR) pathway in the humanmonocyte-macrophage by pathogen-associated membrane patterns, or PAMPs, shed by microbial agents like Mycobacteriumtuberculosis initiate expression of the CYP27B1-hydroxylase and VDR genes in that cell (Fig. 2). If insufficient substrate25OHD is available to the macrophage CYP27B1-hydroxylase, as is the case in vitamin D insufficiency/deficiency (23), theninsufficient product 1,25(OH) D will be generated locally. This, in turn, will diminish binding of 1,25(OH) D to themacrophage VDR, thereby limiting the activation of 1,25-(OH) D-VDR-directed antimicrobial genes (i.e. cathelicidin) andassociated killing of ingested microbe. These events appear to be borne out in a metaanalysis of M. tuberculosis infectionrates (effect sizes) in humans; compared with matched control subjects from the same population, patients with activetuberculosis possessed significantly lower serum 25OHD levels (24). These kinds of data with tuberculosis have promptedinvestigators to look at the effect of low 25OHD levels on other microbial infections. For example, Ginde et al. (25) recentlydemonstrated that the prevalence of upper respiratory tract infections in the NHANES III population 1) increasedsignificantly, regardless of season of the year, as the serum 25OHD dropped; and 2) was greatest during winter months when25OHD levels were at their lowest. Other recent studies have shown that 1,25-(OH) D-directed production of cathelicidin isnot restricted to monocyte-macrophages. Indeed, this appears to involve an antimicrobial mechanism also employed byepithelial cells from a variety of tissue “barrier” sites, like the gut (26), lung (27), placenta (28), and skin (29,30,31,32). Incontrast to the stimulation of antibacterial responses by vitamin D, its impact on viral infection is much less clear. However,the ability of viruses to activate TLR-induced pathways similar to those activated by mycobacteria and bacteria suggests thatinduction of intracrine immune responses to vitamin D may also promote antiviral activity.
All-cause and cardiovascular mortality
Although low 25OHD levels have been known to be associated for some time now with colon cancer mortality (33), onlyrecently have data emerged demonstrating that vitamin D insufficiency/deficiency is significantly associated with all-causemortality, at least in the American population (Table 1). The NHANES III database clearly shows: 1) an increase in adjustedall-cause mortality as the serum 25OHD level falls to less than 30 ng/ml, especially in women; and 2) peak protection fromdeath with a 25OHD level in the 35–40 ng/ml range. In fact, most of the increase in all-cause mortality can be attributed tocardiovascular disease deaths in this population (Table 1). The prevalence of coronary artery disease, heart failure, andperipheral artery disease is significantly increased in a stepwise fashion as the serum 25OHD level drops to less than 30 andthen 20 ng/ml (34).
Metabolic disease
Inspection of the recent vitamin D insufficiency/deficiency epidemiological literature has brought to light the striking inversecorrelation of the 25OHD level not only to cardiovascular disease but also to essentially all of the elements of the humanmetabolic syndrome (Table 1): 1) hypertension; 2) obesity; 3) insulin resistance and glucose intolerance. In fact, the onlyage-adjusted trend in the NHANES population that matches the magnitude of the rate of decrease in the serum 25OHD level
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over time is the rate of increase in the BMI in that period (National Center for Health Statistics, 2009). If one looks at theNHANES III data set, there is a significant stepwise quartile drop in the serum 25OHD level with the reverse quartile trendupward in both percentage body weight and BMI in that population (12). A similar trend can be observed in smaller studiesof adolescents, particularly postpubertal females of Hispanic ethnicity (35).
Is There a Vitamin D:Fat:Bone Axis in Humans?
The preceding discussion with regard to the “association” of increasing adiposity and its metabolic consequences (e.g.cardiovascular disease) with vitamin D insufficiency/deficiency begs the question of whether there is a causal link betweenthe two. For example, it has recently been shown that the serum 25OHD level rises significantly in extremely obese patientsafter undergoing intestinal bypass surgery (36) that induces a rapid reduction in fat mass in the host. These observationssuggest that low 25OHD levels observed in association with obesity may be due in part to: 1) the increased volume ofdistribution to fat of lipid soluble vitamin D as it leaves the general circulation after being synthesized in the skin or obtainedthrough the diet; and 2) preferential retention of vitamin D in those fat stores. Although not yet performed in vivo in humans,studies with mice also indicate that: 1) vitamin D deficiency, in and of itself, increases body weight (Hewison, M.,unpublished data); and 2) null mutations in the VDR or the CYP27B1α-hydroxylase have the opposite effect, to preventabdominal fat mass accumulation and weight gain in mice on a normal chow (37) and as well as on a high-fat diet (38). Asdepicted in Fig. 3A, these data suggest that systemic 25OHD deficiency, which is known to result in secondaryhyperparathyroidism and stimulation of the renal CYP27B1-hydroxylase, is associated with maintenance of the serum1,25(OH) D in the normal range (7) until the substrate 25OHD level in blood drops to less than 10 nmol/liter or 4 ng/ml (39).Acting through the VDR, these events result in an increase in fat mass by yet unknown means. It is hypothesized that thisincrease in body fat mass acts in a “feed-forward” fashion to further increase the volume of distribution for vitamin D,deepen the state of vitamin D deficiency, and amplify the consequences of secondary hyperparathyroidism on the skeleton(Fig. 1A) and body fat. There are some data now (40) to suggest that there exists a leptin-mediated “negative feedback” loopto interrupt this cycle of fat accumulation. It is well known that an increase in fat mass is associated with increasedfat-derived, serum leptin. Leptin may act as a brake on this cycle by providing a means of static inhibition of CYP27B1 geneexpression and 1-hydroxylase enzyme activity in the kidney and/or adipose tissue itself (41).
Vitamin D Replacement
Restoration of serum 25OHD to normal
Although cause-and-effect data from human studies are still lacking, there is reason to believe from the above presentedpopulation association and small animal analyses that there is sound rationale for avoiding vitamin D depletion. That beingthe case and because vitamin D (i.e. 25OHD) insufficiency/deficiency is rampant worldwide, how does one go about: 1)replenishing vitamin D stores, and 2) maintaining normal 25OHD levels thereafter? Figure 3B depicts the therapeuticreplacement strategy that we employ for our clinical studies (23,42). After first measuring the serum calcium, 25OHD, andiPTH level to establish the presence or absence of vitamin D insufficiency/deficiency and degree of secondaryhyperparathyroidism if present, and second, ruling out underlying hypercalcemia, hypercalciuria, and primaryhyperparathyroidism, the subject receives 500,000 IU vitamin D (see Footnote 1) orally in divided 50,000 IU doses over thecourse of 4 to 5 wk. After a second 4- to 5-wk period of equilibration without drug to permit stabilization of the serum25OHD concentration, the serum 25OHD level is obtained to determine whether levels are greater than 30 ng/ml. If so, thesubject is given 50,000 IU ergocalciferol (vitamin D ) (43) or cholecalciferol (vitamin D ) orally on a monthly basis tomaintain vitamin D sufficiency. The serum 25OHD is monitored annually to ensure sufficiency. The serum iPTH is alsoredetermined at this interval to ensure that it has not increased from baseline, which may be indicative of coexistent primaryhyperparathyroidism, a not uncommon occurrence (44). If the 25OHD does not normalize at the 10- to 12-wk mark, thereplacement and monitoring regimen is repeated. If the serum 25OHD is still subnormal after two rounds of vitamin Dreplacement and compliance with the treatment regimen is documented, then a search for and treatment of intestinal fatmalabsorption is undertaken. Considering that parenteral delivery of vitamin D is no longer an option in the United States, aprogram of more vigorous oral vitamin D supplementation or carefully graded whole body UVB radiation exposure (45) is atherapeutic option.
Controversy exists as to whether replacement therapy should be achieved with ergocalciferol (vitamin D ) or cholecalciferol(vitamin D ). A study performed early in the decade showed that a 50,000-IU oral dose of vitamin D , compared with thesame oral dose of vitamin D , first seemed to be associated with a higher volume of distribution and/or less effectiveconversion to 25OHD (e.g. lower peak blood levels of 25OHD after dosing); and second, that there was more rapidclearance of converted 25OHD from the serum (46). There was no mention in this study as to whether subjects taking
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vitamin D and vitamin D were matched for basal 25OHD concentration or BMI. A more recent study by Holick et al. (47)of vitamin D-insufficient subjects given much smaller daily doses (1000 IU) of vitamin D , vitamin D , a combination ofvitamin D and vitamin D (500 IU each), or placebo for 11 wk showed no difference in the incremental increase in total25OHD levels among the vitamin D treatment regimens; all significantly increased the serum 25OHD, albeit not to the25OHD-sufficient range (>30 ng/ml). There was no assessment of a vitamin D-specific bioresponse in either of these studies.As a consequence of the above, all of our currently active, prospective vitamin D replacement trials compare the oraladministration vitamin D (Swanson Health Products; not FDA-approved) and vitamin D preparations (Calciferol, SchwartzPharma; FDA-approved) each at a concentration of 1000 IU (in vegetable oil) per drop and use a relevant biomarker ofvitamin D action (e.g. serum iPTH for skeletal and ex vivo host macrophage cathelicidin gene expression (23) (see Fig. 2 forinnate immunity outcomes).
Maintenance of 25OHD sufficiency
Maintenance of vitamin D sufficiency has become a substantial problem because of: 1) self-imposed limitations on sunlightexposure; 2) the current underestimates for recommended daily intake of vitamin D (100–800 IU daily depending on age anddisease); 3) the relative scarcity of vitamin D in our diets (see below); and perhaps iv) increasing body fat mass inpopulations around the world. The most plentiful natural sources of vitamin D and vitamin D in our diet are derived fromwild-caught, not farm-raised, fatty fishes like salmon (∼1,000 IU per 3.5 ounces; Ref. 48) and UVB-exposed fungoids (i.e.mushrooms; up to 100,000 IU per 3.5 ounces; Ref. 49), respectively. However, because of expense and lack of qualitycontrol over vitamin D content of cultivated products, neither fish nor irradiated mushroom ingestion is currentlyrecommended as a reliable means of vitamin D supplementation, especially if one considers the fact that the newrecommended daily intake for vitamin D intake to maintain vitamin sufficiency is likely to increase significantly in the nearfuture (www.iom.edu). As such, in the absence of sufficient cutaneous vitamin D production, maintenance of vitamin Dsufficiency is routinely achieved by the daily consumption of dietary supplements containing synthetic vitamin D or vitaminD .
Measuring 25OHD
There is also substantial controversy regarding the best commercial methodology for measuring 25OHD in the serum ofhumans (50). Immunoassay remains the “gold standard.” It has been employed by most of the large-scale population studiesperformed in the recent past in the United States (e.g. NHANES and the Women’s Health Initiative). This assay technologymeasures total 25OHD after solid-phase extraction of the serum. It measures 25OHD and 25OHD equally well and doesnot discriminate between the two. Liquid chromatography-tandem mass spectrometric analysis requires lipid extraction ofthe serum before assay and measures 25OHD and 25OHD separately. It is the fastest growing method; however, normativestandards for commercially available assays are not yet published. Finally, HPLC is employed by a few commercial labs.Like liquid chromatography-tandem mass spectrometric analysis, it requires lipid extraction of the serum and measures25OHD and 25OHD separately. Normative standards exist, but the technology is hampered by the fact that it istime-consuming and expensive.
Conclusions
The last year in clinical vitamin D research has confirmed the presence of a worldwide problem with vitamin D depletion, aproblem that appears to be worsening. Large-scale population studies bear out long-held concerns that low serum 25OHDlevels are associated with a number of adverse outcomes in the human musculoskeletal, innate immune, and cardiovascularsystems; in fact, low vitamin D levels are significantly associated with all-cause mortality in the U.S. population. It ishypothesized that the rise in global obesity contributes to the worsening of the problem of vitamin Dinsufficiency/deficiency, amplifying adverse impacts on the host skeleton, immunoreactivity to microbes, and metabolicstatus. Because of its frequency, its ease of detection, its associated adverse outcomes, and the straightforward, inexpensiveand effective means by which is can be treated, vitamin D insufficiency should be sought especially when evaluating andtreating osteoporotic, otherwise immuno-compromised, and obese subjects. Finally, it should be remembered that treatmentof vitamin D insufficiency/deficiency has two phases: 1) restoration of 25OHD levels to more than 30 ng/ml; and 2)maintenance of the serum 25OHD in that range.
Footnotes
This work was supported by Grants RO1 AR037399-22, RO1 AR050626-05, RO1 AI073539-02, and RO1 EB009306-02 from NationalInstitutes of Health.
Disclosure Summary: The authors have nothing to disclose.
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Expression of vitamin D or vitamin D metabolites without a subscript refers to the total compliment of both vitamin D and vitamin D ortotal compliment of vitamin D and vitamin D metabolites, respectively, in the sample.
Abbreviations: BMI, Body mass index; FGF23, fibroblast growth factor 23; iPTH, immunoreactive PTH; 1,25(OH) D, 1,25-dihydroxyvitaminD; OHD, 25-hydroxyvitamin D; TLR, Toll-like receptor; VDR, vitamin D receptor.
References
Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG,Lips P, Morales-Torres J 2009 Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int20:1807–1820
1.
Kuchuk NO, van Schoor NM, Pluijm SM, Chines A, Lips P 2009 Vitamin D status, parathyroid function, boneturnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res 24:693–701
2.
Hewison M 2008 Vitamin D and innate immunity. Curr Opin Investig Drugs 9:485–4903. Holick MF 2008 Vitamin D: a D-lightful health perspective. Nutr Rev 66:S182–1944. Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW 2008 Structural analysis of CYP2R1 in complexwith vitamin D3. J Mol Biol 380:95–106
5.
Chun RF, Adams JS, Hewison M 2008 Back to the future: a new look at ‘old’ vitamin D. J Endocrinol 198:261–269[PMCID: PMC2699326]
6.
Quarles LD 2008 Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 118:3820–3828[PMCID: PMC2586800]
7.
Adams JS, Hewison M 2008 Unexpected actions of vitamin D: new perspectives on the regulation of innate andadaptive immunity. Nat Clin Pract Endocrinol Metab 4:80–90 [PMCID: PMC2678245]
8.
Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, Meinken C, KamenDL, Wagner M, Bals R, Steinmeyer A, Zügel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS,Bloom BR, Modlin RL 2006 Activation of human TLR2/1 triggers a vitamin D receptor-dependent antimicrobialresponse. Science 311:1770–1773
9.
Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, Meunier PJ 1997 Prevalence of vitamin Dinsufficiency in an adult normal population. Osteoporos Int 7:439–443
10.
Ginde AA, Liu MC, Camargo Jr CA 2009 Demographic differences and trends of vitamin D insufficiency in theUS population, 1988–2004. Arch Intern Med 169:626–632 [PMCID: PMC3447083]
11.
Yetley EA 2008 Assessing the vitamin D status of the US population. Am J Clin Nutr 88:558S–564S12. Greer FR 2008 25-Hydroxyvitamin D: functional outcomes in infants and young children. Am J Clin Nutr88:529S–533S
13.
Looker AC, Pfeiffer CM, Lacher DA, Schleicher RL, Picciano MF, Yetley EA 2008 Serum 25-hydroxyvitamin Dstatus of the US population: 1988–1994 compared with 2000–2004. Am J Clin Nutr 88:1519–1527[PMCID: PMC2745830]
14.
Mozolowski W 1939 Jedrzej Sniadecki (1768–1838) on the cure of rickets. Nature 143:12115. Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, Orav JE, Li R, Spiegelman D, Dietrich T, Willett WC 2009Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among U.S. adults. J Bone Miner Res24:935–942 [PMCID: PMC3312737]
16.
Bischoff-Ferrari HA, Willett WC, Wong JB, Stuck AE, Staehelin HB, Orav EJ, Thoma A, Kiel DP,Henschkowski J 2009 Prevention of nonvertebral fractures with oral vitamin D and dose dependency: ameta-analysis of randomized controlled trials. Arch Intern Med 169:551–561
17.
Cauley JA, Lacroix AZ, Wu L, Horwitz M, Danielson ME, Bauer DC, Lee JS, Jackson RD, Robbins JA, Wu C,Stanczyk FZ, LeBoff MS, Wactawski-Wende J, Sarto G, Ockene J, Cummings SR 2008 Serum25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 149:242–250[PMCID: PMC2743412]
18.
Mahon P, Harvey N, Crozier S, Inskip H, Robinson S, Arden N, Swaminathan R, Cooper C, Godfrey K 2009Low maternal vitamin D status and fetal bone development: a cohort study. J Bone Miner Res doi:10.1359/jbmr.090701 [PMCID: PMC4768344]
19.
Liu PT, Stenger S, Tang DH, Modlin RL 2007 Cutting edge: vitamin D-mediated human antimicrobial activityagainst Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179:2060–2063
20.
Krutzik SR, Hewison M, Liu PT, Robles JA, Stenger S, Adams JS, Modlin RL 2008 IL-15 links TLR2/1-inducedmacrophage differentiation to the vitamin D-dependent antimicrobial pathway. J Immunol 181:7115–7120[PMCID: PMC2678236]
21.
Liu PT, Schenk M, Walker VP, Dempsey PW, Kanchanapoomi M, Wheelwright M, Vazirnia A, Zhang X,22.
a2 3
2 3
2
Update in Vitamin D http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840860/?report=pr...
6 of 12 5/24/16 10:42 PM
Steinmeyer A, Zügel U, Hollis BW, Cheng G, Modlin RL 2009 Convergence of IL-1ß and VDR activationpathways in human TLR2/1-induced antimicrobial responses. PLoS One 4:e5810 [PMCID: PMC2686169]Adams JS, Ren S, Liu PT, Chun RF, Lagishetty V, Gombart AF, Borregaard N, Modlin RL, Hewison M 2009Vitamin D-directed rheostatic regulation of monocyte antibacterial responses. J Immunol 182:4289–4295[PMCID: PMC2683618]
23.
Nnoaham KE, Clarke A 2008 Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis.Int J Epidemiol 37:113–119
24.
Ginde AA, Mansbach JM, Camargo Jr CA 2009 Association between serum 25-hydroxyvitamin D level and upperrespiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med169:384–390 [PMCID: PMC3447082]
25.
Liu N, Nguyen L, Chun RF, Lagishetty V, Ren S, Wu S, Hollis B, DeLuca HF, Adams JS, Hewison M 2008Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation.Endocrinology 149:4799–4808 [PMCID: PMC2582909]
26.
Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW 2008 Respiratory epithelial cellsconvert inactive vitamin D to its active form: potential effects on host defense. J Immunol 181:7090–7099[PMCID: PMC2596683]
27.
Liu N, Kaplan AT, Low J, Nguyen L, Liu GY, Equils O, Hewison M 2009 Vitamin D induces innate antibacterialresponses in human trophoblasts via an intracrine pathway. Biol Reprod 80:398–406 [PMCID: PMC2704027]
28.
Schauber J, Oda Y, Büchau AS, Yun QC, Steinmeyer A, Zügel U, Bikle DD, Gallo RL 2008 Histone acetylationin keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D . J InvestDermatol 128:816–824
29.
Segaert S 2008 Vitamin D regulation of cathelicidin in the skin: toward a renaissance of vitamin D in dermatology? JInvest Dermatol 128:773–775
30.
Peric M, Koglin S, Kim SM, Morizane S, Besch R, Prinz JC, Ruzicka T, Gallo RL, Schauber J 2008 IL-17Aenhances vitamin D -induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J Immunol181:8504–8512 [PMCID: PMC2655307]
31.
Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Büchau A, Steinmeyer A, Zügel U, Ruzicka T,Schauber J 2009 Vitamin D analogs differentially control antimicrobial peptide “alarmin” expression in psoriasis.PLoS One 4:e6340 [PMCID: PMC2709447]
32.
Wu K, Feskanich D, Fuchs CS, Willett WC, Hollis BW, Giovannucci EL 2007 A nested case control study ofplasma 25-hydroxyvitamin D concentrations and risk of colorectal cancer. J Natl Cancer Inst 99:1120–1129
33.
Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ 2008 Prevalence of hypovitaminosis D in cardiovasculardiseases (from the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol 102:1540–1544
34.
Kremer R, Campbell PP, Reinhardt T, Gilsanz V 2009 Vitamin D status and its relationship to body fat, finalheight, and peak bone mass in young women. J Clin Endocrinol Metab 94:67–73 [PMCID: PMC2630864]
35.
de Luis DA, Pacheco D, Izaola O, Terroba MC, Cuellar L, Martin T 2008 Clinical results and nutritionalconsequences of biliopancreatic diversion: three years of follow-up. Ann Nutr Metab 53:234–239
36.
Narvaez CJ, Matthews D, Broun E, Chan M, Welsh J 2009 Lean phenotype and resistance to diet-induced obesityin vitamin D receptor knockout mice correlates with induction of uncoupling protein-1 in white adipose tissue.Endocrinology 150:651–661 [PMCID: PMC2646525]
37.
Wong KE, Szeto FL, Zhang W, Ye H, Kong J, Zhang Z, Sun XJ, Li YC 2009 Involvement of the vitamin Dreceptor in energy metabolism: regulation of uncoupling proteins. Am J Physiol Endocrinol Metab 296:E820–E828[PMCID: PMC2670625]
38.
Need AG, O'Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE 2008 Vitamin D metabolites andcalcium absorption in severe vitamin D deficiency. J Bone Miner Res 23:1859–1863
39.
Matsunuma A, Horiuchi N 2007 Leptin attenuates gene expression for renal 25-hydroxyvitamin D3–1α-hydroxylasein mice via the long form of the leptin receptor. Arch Biochem Biophys 463:118–127
40.
Li J, Byrne ME, Chang E, Jiang Y, Donkin SS, Buhman KK, Burgess JR, Teegarden D 2008 1α,25-Dihydroxyvitamin D hydroxylase in adipocytes. J Steroid Biochem Mol Biol 112:122–126 [PMCID: PMC2602794]
41.
Geller JL, Hu B, Reed S, Mirocha J, Adams JS 2008 Increase in bone mass after correction of vitamin Dinsufficiency in bisphosphonate-treated patients. Endocr Pract 14:293–297
42.
Pepper KJ, Judd SE, Nanes MS, Tangpricha V 2009 Evaluation of vitamin D repletion regimens to correct vitaminD status in adults. Endocr Pract 15:95–103 [PMCID: PMC2683376]
43.
Eastell R, Arnold A, Brandi ML, Brown EM, D'Amour P, Hanley DA, Rao DS, Rubin MR, Goltzman D,Silverberg SJ, Marx SJ, Peacock M, Mosekilde L, Bouillon R, Lewiecki EM 2009 Diagnosis of asymptomatic
44.
3
3
Update in Vitamin D http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840860/?report=pr...
7 of 12 5/24/16 10:42 PM
primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 94:340–350Khazai NB, Judd SE, Jeng L, Wolfenden LL, Stecenko A, Ziegler TR, Tangpricha V 2009 Treatment andprevention of vitamin D insufficiency in cystic fibrosis patients: comparative efficacy of ergocalciferol,cholecalciferol, and UV light. J Clin Endocrinol Metab 94:2037–2043 [PMCID: PMC2690417]
45.
Armas LA, Hollis BW, Heaney RP 2004 Vitamin D is much less effective than vitamin D in humans. J ClinEndocrinol Metab 89:5387–5391
46.
Holick MF, Biancuzzo RM, Chen TC, Klein EK, Young A, Bibuld D, Reitz R, Salameh W, Ameri A,Tannenbaum AD 2008 Vitamin D is as effective as vitamin D in maintaining circulating concentrations of25-hydroxyvitamin D. J Clin Endocrinol Metab 93:677–681 [PMCID: PMC2266966]
47.
Chen TC, Chimeh F, Lu Z, Mathieu J, Person KS, Zhang A, Kohn N, Martinello S, Berkowitz R, Holick MF2007 Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Arch Biochem Biophys460:213–217 [PMCID: PMC2698590]
48.
Roberts JS, Teichert A, McHugh TH 2008 Vitamin D formation from post-harvest UV-B treatment of mushrooms(Agaricus bisporus) and retention during storage. J Agric Food Chem 56:4541–4544
49.
Hollis BW 2008 Measuring 25-hydroxyvitamin D in a clinical environment: challenges and needs. Am J Clin Nutr88:507S–510S
50.
Figures and Tables
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Figure 1
A, Summary of distinctions between the two, phylogentically discrete functions of vitamin D (see Footnote 1), one as a circulating hormone(left) and the other as a locally produced, locally active cytokine made by monocyte-macrophages (right). B, Schematic tracing the serialendocrine responses to a diminishment in vitamin D-directed intestinal calcium absorption as might be seen in humans with acquired vitaminD insufficiency/deficiency; the final step in the process is 1,25-dihydroxyvitamin D (1,25-D) stimulation of genes controlling calciumabsorption from the gut, mobilization of calcium from the skeleton and, finally, synthesis and release of FGF23, which acts to return previouslyenhanced PTH and CYP27B1-hydroxylase gene expression to normal. DBP, Vitamin D binding protein; RXR, retinoid X receptor.
Update in Vitamin D http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840860/?report=pr...
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Figure 2
Shown is a schematic of a human macrophage responding to pathogen-associated membrane patterns (PAMPs), shed from wall of M.tuberculosis via the pattern recognition, TLR dimmer pair, TLR1–TLR2. Signaling through the TLRs leads to induction of expression of theendogenous CYP27B1-hydroxylase and VDR. Provided that adequate amounts of substrate 25-hydroxyvitamin D (25D), circulated to themonocyte-macrophage bound to the serum vitamin D binding protein (DBP), are available to the mitochondrial CYP27B1 for intracrineconversion to 1,25-dihydroxyvitamin D (1,25D), the 1,25D ligand activates the VDR; instigates its dimerization with retinoid X receptor(RXR) and nuclear localization of the VDR-RXR; and promotes expression of the cathelicidin antimicrobial gene. In turn, the cathelicidingene product, LL37, supports the phagolysosomal killing of ingested mycobacterium.
Update in Vitamin D http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840860/?report=pr...
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Figure 3
A, Proposed schema linking low serum 25D levels and secondary hyperparathyroidism with 1,25-dihydroxyvitamin D (1,25D)-driven fataccumulation amplifying the state of vitamin D depletion, while at the same time generating an increase in the serum leptin concentration,which exerts feedback inhibition on the synthesis of 1,25D. B, Schematic of the regimen for vitamin D replacement and maintenance therapyin subjects with serum 25D levels less than 30 ng/ml. The regimen calls for: 1) delivery of 500,000 to 1,000,000 IU vitamin D (see Footnote 1)orally over 4–5 wk; 2) a similarly timed period of no vitamin D to permit ascertainment and confirmation of steady-state 25D levels; and 3)maintenance therapy of 50,000 IU vitamin D orally every month thereafter to maintain a vitamin D sufficiency.
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Table 1
Recent association studies demonstrating a significant inverse correlation between the serum 25D level and an increase incomponents of the human metabolic syndrome
Mortality causes First author Year Ref.
All causes Melamed 2008 Arch Intern Med 168:1629
Dobnig 2008 Arch Intern Med 168:1340
Cardiovascular disease Kim 2008 Am J Cardiol 102:1540 (34)
Wang 2008 Circulation 117:503
Kendrick 2009 Atherosclerosis 205:255
Hypertension Judd 2008 Am J Clin Nutr 87:136
BMI Looker 2008 Am J Clin Nutr 88:1519 (14)
Insulin resistance Liu 2009 J Nutr 139:329
Wu 2009 J Nutr 139:547
Articles from The Journal of Clinical Endocrinology and Metabolism are provided here courtesy of The Endocrine Society
Update in Vitamin D http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840860/?report=pr...
